5-Mercaptoalkyl-1,2,4-oxadiazole derivatives

ABSTRACT

AND SALTS THEREOF, ARE USEFUL AS ANTI-INFLAMMATORY AGENTS.   5-Mercaptoalkyl-1,2,4-oxadiazole derivatives of the general formula

United States Patent [191 Breuer et al.

[ June 3, 1975 S-MERCAPTOALKYL-1,2,4-OXADIAZOLE DERIVATIVES [75]Inventors: Hermann Breuer; Uwe D. Treuner,

both of Regensburg, Germany [73] Assignee: E. R. Squibb & Sons, Inc.,

Princeton, NJ.

[22] Filed: Jan. 5, 1973 [21] Appl. No.: 321,419

[56] References Cited OTHER PUBLICATIONS Smith Open Chain NitrogenCompounds Vol. 1, (1965), W. A. Benjamin, Inc., New York, pp. 276-7.

Primary ExaminerDonald G. Daus Assistant Examiner-Raymond V. RushAttorney, Agent, or Firm-Lawrence S. Levinson; Merle J. Smith 57ABSTRACT S-Mercaptoalkyl-l,2,4-oxadiazole derivatives of the generalformula and salts thereof, are useful as anti-inflammatory agents.

9 Claims, No Drawings I S-MERCAPTOALKYL-l ,2,4-OXADIAZOLE DERIVATIVESSUMMARY OF THE INVENTION This invention relates to new S-mercaptoalkyl-l,2,4- oxadiazole derivatives of the formula wherein R is lower alkyl,lower alkenyl, cyclo-lower alkyl, phenyl, substituted phenyl,phenyl-lower alkyl, substituted phenyl-lower alkyl or phenyl-loweralkenyl; R R R R and R which may be the same or different, are hydrogenor lower alkyl; the radical also is one of the heterocyclics piperidino,morpholino, thiamorpholino, piperazino or pyrrolidino; and n is l, 2 or3.

The preferred compounds of this class are those wherein R, is loweralkyl, especially methyl, phenyl or phenyl-lower alkyl, R and R arehydrogen or lower alkyl, especially hydrogen, R R and R are hydrogen orlower alkyl, especially methyl, and n is l or 2, especially 1.

DETAILED DESCRIPTION OF THE INVENTION The lower alkyl groups representedby the various symbols are straight or branched chain saturatedhydrocarbon radicals of one to seven carbon atoms, preferably one tothree carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl,t-butyl and the like. The lower alkenyl groups are mono-unsaturatedhydrocarbon radicals of the same kind. The cyclolower alkyl groups arethe three to six carbon alicyclics cyclopropyl, cyclobutyl, cyclopentyland cyclohexyl, the last two being preferred.

The substituted phenyl radicals are monosubstituted phenyl groups, i.e.,R -phenyl wherein R is lower alkyl, halo (preferably chloro or bromo) orlower alkoxy (preferably methoxy), especially in the para-position.

The phenyl-lower alkyl and phenyl-lower alkenyl groups have a phenylgroup attached to a lower alkyl or lower alkenyl group of the typedescribed above, respectively. Examples are benzyl, phenethyl,phenylpropyl, styryl, cinnamyl, etc.

The substituted phenyl-lower alkyl radicals include the samesubstituents as the substituted phenyl radicals, i.e., R -phenyl-loweralkyl, wherein R is similarly lower alkyl (especially preferred), halo(preferably chloro or bromo) or lower alkoxy (preferably methoxy),particularly in the para-position. Especially preferred are the loweralkyl groups (both on the phenyl and joining the phenyl to theoxadiazole) having one to four carbons.

The heterocyclics represented by the group are named above.

The compounds of formula I form acid addition salts with a variety ofinorganic and organic acids. These salts include the hydrohalides(especially hydrochloride and hydrobromide), sulfate, nitrate, borate,phosphate, oxalate, tartrate, malate, citrate, acetate, ascorbate,succinate, benzenesulfonate, methanesulfonate, cyclohexanesulfamate andtoluenesulfonate. The acid addition salts frequently provide aconvenient means for isolating the product, e.g., by forming andprecipitating the salt in an appropriate menstruum in which the salt isinsoluble, then after separation of the salt, neutralizing with a basesuch as barium hydroxide or sodium hydroxide, to obtain the free base offormula I. Other salts may then be formed from the free base by reactionwith one or more equivalents of acid. They are preferably isolated andused in the form of a salt, the hydrochloride being the first choice. i

The compounds of this invention are useful as antiinflarnmatory agentsand are effective in the prevention and inhibition of granuloma tissueformation in warm blooded animals, for example, in a manner similar toindomethacin. They may be used to decrease joint swelling tenderness,pain and stiffness, in mammalian species, e.g., in conditions such asrheumatoid arthritis. A compound of this invention or a physiologicallyacceptable acid addition salt of the character described above may becompounded according to accepted pharmaceutical practice in oral dosageforms such as tablets, capsules, elixirs or powders for administrationof about mg to 2 gm per day, preferably 100 mg to 1 gm per day, in twoto four divided doses. For example, about 15 mg/kg/day is effective inreducing paw swelling in rats. v

The new compounds of formula I are produced from S-haloalkyl-l,2,4-oxadiazole derivatives of the formula by reaction with a thioureaderivative of the formula (III) c 4 NH 1 Nnou by reaction with an acidhalide of the formula (v) c co-x As a result of this reaction, anintermediate of the following formula forms /NH (VI) R -c then watersplits off and cyclization occurs yielding the material of formula II.See, for example, Fortschritte der chemischen Forschung 4 (No. 4), 810(1965). Other members of the group are formed by the above illustrativeprocedure.

The following examples are illustrative of the invention. Alltemperatures are on the centigrade scale.

EXAMPLE 1 3-Methyl-5-( amidinomercaptomethyl )-1 ,2,4- oxadiazole,hydrochloride 7.6 g. of thiourea are brought into solution in 60 ml. ofethanol by warming. The solution is permitted to cool whereupon thethiourea separates in a finely divided form. To this suspension areadded 13.3 g (0.1 mol) of 3-methyl-5-chloromethyl-1,2,4-oxadiazole andthe mixture is stirred overnight. The thiourea gradually goes intosolution. On the second day new crystals sep arate. 9.7 g of3-methyl-5-(amidinomercaptomethyl)- 1,2,4-oxadiazole, hydrochloride,m.p. l53l54, are obtained. By adding ether to the mother liquor anadditional 8.3 g. of product, m.p. l49l50, are obtained.

EXAMPLE 2 3-Phenyl-5-(amidinomercaptomethyl)-l ,2,4- oxadiazole,hydrochloride 40.4 g (0.2 mol) of 3-phenyl-5-chloromethyl-1,2,4-oxadiazole are added to a suspension of 15.2 g of finely dividedthiourea in 300 ml. of ethanol and the mixture is allowed to stand atroom temperature for 20 hours. 3-Phenyl-5-( amidinomercaptomethyl)-l,2,4-

4 oxadiazole, hydrochloride, crystallizes, m.p. 17l173, yield 49.5 g. 1

EXAMPLE 33-Phenyl-5-(N,N,N-trimethylamidinomercaptomethyl)-1,2,4-oxadiazole,hydrochloride 2.4 g. of N,N,N'-trimethylthiourea and 4.04 g. of 3-phenyl-S-chloromethyl-l,2,4-oxadiazole are dissolved in 50 ml. ofmethylene chloride and heated at 40 for three days. The precipitate isfiltered under suction to obtain 4.3 g. of 3-phenyl-5-(N,N,N'-trimethylamidinomercaptomethyl )-l ,2,4-oxadiazole, hydrochloride, m.p.162l64.

EXAMPLE 4 3-Phenyl-5-(2-amidinomercaptoethyl)-1 ,2,4- oxadiazole,hydrochloride A solution of 9.95 g. of 3-phenyl-5-( 2-chloroethyl)-1,2,4-oxadiazole and 3.8 g. of thiourea are refluxed for three days. Theraction mixture is concentrated in a rotary evaporator and the residueis triturated with ether. The ether insoluble portion is crystallizedfrom isopro panol to obtain 6.5 g. of 3-phenyl-5-(2-amidinomercaptoethyl)-1,2,4-oxadiazole, hydrochloride, m.p. l60-l61.

EXAMPLE 5 3-p-Chlorophenyl-5-( amidinomercaptomethyl)-l ,2,4-oxadiazole, hydrochloride By substituting3-p-chlorophenyl-5-chloromethyl- 1,2,4-oxadiazole as the startingmaterial in the procedure of Example 2a, 3-p-chlorophenyl-5-(amidinomercaptomethyl)-l ,2,4-oxadiazole, hydrochloride, is obtained,m.p. 195 (dec).

EXAMPLE 6 3-p-Methoxyphenyl-5-(amidinomercaptomethyl)- l,2,4-oxadiazole,hydrochloride By substituting 3-p-methoxyphenyl-S-chloromethyl-1,2,4-oxadiazole as the starting material in the procedure of Example2a, 3-p-methoxyphenyl-5- chloromethyl-l,2,4-oxadiazole, hydrochloride,is obtained, m.p. 182 (dec).

EXAMPLE 7 a. DL-3-(a-Phenylpropyl)-5-chloromethyl-1,2,4- oxadiazole 100g. of a-phenylbutyrylnitrile are added to a solution of 27.3 g. ofhydroxylamine in 620 ml. of ethanol and the mixture is permitted tostand for two days at room temperature. This is then concentrated in therotary evaporator. The residue is taken up in ether and the ether phaseis extracted with 4X10O ml. of 2N hydrochloric acid. The hydrochloricacid extracts are combined and adjusted to pH 7-7.5 with 2N sodiumhydroxide solution. The oil which separates is taken up in methylenechloride. The methylene chloride solution is dried with magnesiumsulfate, filtered and g. of pyridine are added. Then g. ofchloracetylchloride are added dropwise with stirring at a temperature of0-5. The mixture is then stirred for three more hours at roomtemperature.

The solvent is evaporated, water is added to the resi' due and it isextracted with 3X200 ml. of toluene. The

toluene extracts are washed with dilute hydrochloric acid and water,dried with magnesium sulfate and heated in a reflux condenser for 3hours to remove water. The solvent is then evaporated and the residue isdistilled under vacuum to obtain 46.3 g. ofDL-3-(aphenylpropyl)-5-chloromethyl-1,2,4-oxadiazole, b.p.( o 109 -1 10.

b. DL-3-(a-phenylpropyl)-5-(amidinomercaptomethyl)- 1,2,4-oxadiazole,hydrochloride By reacting 4.72 g. of DL-3-(a-phenylpropyl)-5- 10 catedin the table or a thiourea having the substituents R R and R indicatedin the table, respectively.

R NR 1 1 5 H 4 c s-c R Example R R2 R3 R4 \R n s 0 H H H r-1H 1 91-C;,H, CH3 H H 1-1H 1 10 .H CH3 CH3 H -1-1H 2 CH 11 CH Q 0 H H -r( 3 112 CH3 cH,, cH,, H r-1H 3 13 H H H NH 2 CH 14 CH H CH 3 1 CH3 15 cH, cHH H NH2 3 l6 cH.,cH=cH H H H NHCl-l 1 H H CH 24 CHpQCH- H H H 7 s-Cntinued s Example RI R2 R R, 6 n

c 26 C H H H C H N 2 5 1 c|-| 27 cH-CH H H H 1 CQHF, I N 33 CH H H CH 1ClH 29 Cl-CH I H H H I 2 What is claimed is: D 3. A compound as in claim1 wherein R is methyl, 1. A compound of the formula R R R R and R. eachis hydrogen and n is l.

4. A compound as in claim 1 wherein R is phenyl,

R R R R R and R each is hydrogen and n is 1. R 5 H 2 4 5. A compound asin claim 1 wherein R is phenyl, R N c C and R each is hydrogen, R R andR each is methyl and n is 1.

R n 6. A compound as in claim 1 wherein R is phenyl,

R6 R R R R and R each is hydrogen and n is 2.

7. A compound as in claim 1 wherein R is pchlorophenyl, R R R R and Reach is hydrogen and n is 1. wherein R is lower alkyl, phenyl,p-chlorophenyl, p- A compound as in Claim 1 wherein R1 is methoxyphenylor Phenyl-lower alkyl, R2, R4, R5 methoxyphenyl, R R R R and R each ishydrogen and R each is hydrogen or lower alkyl, and n is l or 2, and nis said lower alkyl groups having less than four carbon 9 A compound ash claim 1 wherein R i h atomspropyl, R R R R and R each is hydrogen andn is 2. A compound as 1n claim 1 wherein each lower 1 alkyl group ismethyl. 1 g

1. A COMPOUND OF THE FORMULA
 1. A compound of the formula
 2. A compoundas in claim 1 wherein each lower alkyl group is methyl.
 3. A compound asin claim 1 wherein R1 is methyl, R2, R3, R4, R5 and R6 each is hydrogenand n is
 1. 4. A compound as in claim 1 wherein R1, is phenyl, R2, R3,R4, R5 and R6 each is hydrogen and n is
 1. 5. A compound as in claim 1wherein R1 is phenyl, R2 and R3 each is hydrogen, R4R5 and R6 each ismethyl and n is
 1. 6. A compound as in claim 1 wherein R1 is phenyl, R2,R3, R4, R5 and R6 each is hydrogen and n is
 2. 7. A compound as in claim1 wherein R1 is p-chlorophenyl, R2, R3, R4, R5 and R6 each is hydrogenand n is
 1. 8. A compound as in claim 1 wherein R1 is p-methoxyphenyl,R2, R3, R4, R5 and R6 each is hydrogen and n is 1.